Project Summary - CD1 Presentation of Self Lipids to Human T cells ? D. Branch Moody T cells play a central role in the pathogenesis of human autoimmune diseases, including allergy and drug hypersensitivity syndromes. For decades studies of T cell autoantigens have emphasized peptide antigens bound to MHC proteins. This proposal investigates the basis by which self lipid antigens bind to human CD1 antigen presenting molecules, leading to autoreactive T cell responses. This competing renewal builds on an existing program of development that has invented human CD1a and CD1b tetramers and used them to discover previously unknown lipid autoantigens for T cells, including squalene and phosphatidylglycerol. To provide a general basis for lipid epitope mapping, we will use mass spectrometry to broadly identify many hundreds of self lipids that bind to CD1 proteins in human cells. Using tetramers, we will identify and clone autoreactive T cell receptors and measure their binding to CD1-self lipid complexes. Building on recently published studies showing that CD1a autoreactive T cells are increased in patients with allergy syndromes, we will measure CD1a-reactive T cell responses in human cohorts. Finally, we will investigate a new mechanism by which CD1a proteins present common skin irritants from clinical patch tests to T cells, bypassing mechanisms that relate to peptide haptenization. Overall, these studies will extend the spectrum of natural T cell autoantigens to include self lipids and investigate their roles in common allergic diseases.